This application is in response to Program Announcement Number PA-04-074, "Health Disparities in NIDDK Disease." In contrast to the widely reported ethnic differences in prevalence, the incidence of type 2 diabetes was surprisingly similar (~11%) among individuals from the different U.S. ethnic groups in the Diabetes Prevention Program (DPP). Because DPP participants had impaired glucose tolerance (IGT) at baseline, the finding of similar incident diabetes rates led us to hypothesize that ethnic disparities are initiated much earlier during the pathogenesis of type 2 diabetes than is commonly realized. We, therefore, propose to study ethnic disparities proximal to the stage of prediabetes (IGT and impaired fasting glucose {IFG}). We will compare the rates of progression from normal glucose tolerance (NGT) to prediabetes in 200 African-American and 200 Caucasian offspring of parents with type 2 diabetes. Compared with NGT subjects, persons with prediabetes (e.g., IGT) have a two-fold increased risk of fatal cardiovascular disease (CVD). Yet, few prospective studies exist on the natural history, predictors, mechanisms, and mediators of progression from NGT to prediabetes in any population, and none in African-Americans. We argue that focusing on this early period is of public health significance, because the IGT stage may already be too late for complete reversal of metabolic and cardiovascular sequelae. In our proposed study, initially NGT subjects at high risk for type 2 diabetes will undergo repeated metabolic assessments, including glucose tolerance, insulin sensitivity, beta cell function, adipocytokines, CVD risk markers, and socioeconomic and other pertinent endpoints for 5 years. DNA specimens will be stored for future genetic analysis. The primary endpoint is progression from NGT to prediabetes. Secondary endpoints include changes in caloric intake, physical activity, body composition, insulin sensitivity, insulin secretion, lipoproteins, adipocytokines, proinflammatory markers and other known or putative predictors of glycemic dysregulation. By comparing these endpoints between Progressors and Nonprogressors and African-Americans vs. Caucasians we hope to provide novel data on the natural history of prediabetes, and determine whether ethnic disparities are programmed during the transition from NGT to prediabetes. Increased understanding of the various factors that trigger the change from normal glucose to prediabetes would enable the discovery of early preventive interventions before full blown diabetes and its related complications become established. Furthermore, understanding how these factors differ across ethnic groups will improve our ability to better target preventive measures in different communities. [unreadable] [unreadable] [unreadable]